Major depressive illness is a devastating disorder with broad socioeconomic effects. Although pharmacological treatments for depression have been available for over 40 years, these drugs are not always effective and they require chronic administration. The acute actions of most antidepressants occur via inhibition of the reuptake or breakdown of norepinephrine (NE) and serotonin (5-HT), but the mechanisms underlying the therapeutic actions of chronic antidepressants remain largely unknown. The requirement for chronic treatment has lead to the hypothesis that cellular and molecular adaptations to elevated levels of NE and 5-HT mediate the therapeutic response to antidepressants. Identification of the critical adaptations could provide information for the development of faster acting and more efficacious antidepressants. Recent studies from our laboratory have provided evidence that up-regulation of the cAMP signal transduction cascade contributes to the action of antidepressant treatment. Chronic antidepressant treatment increases the expression of the cAMP-response element binding protein (CREB) in limbic brain regions. In addition, the expression of brain derived neurotrophic factor (BDNF) is up regulated, suggesting that BDNF is a gene target of CREB and antidepressant treatment. These effects are observed in response to administration of both NE and 5-HT selective reuptake inhibitors, suggesting that the cAMP-CREB cascade and expression of BDNF are common targets of antidepressant treatment. In this competing renewal, studies are proposed to extend these findings and to test the hypothesis that activation of the cAMP-CBEB cascade and induction of BDNF mediate the action of antidepressant treatment. This will include studies to further characterize the regulation of CREB and BDNF function and expression in vivo and in primary neuronal cultures. Moreover, a major goal of this proposal is to directly test the influence of CREB and BDNF on antidepressant-responsive models, including the forced swim test and learned helplessness paradigms. To modulate levels of CREB and BDNF in the brains of adult animals, two complementary approaches will be used: viral expression in rats and inducible, region specific transgenic mice. Finally, studies to identify the isoforms of cAMP phophodiesterase (PDE4) that catalyzes the breakdown of cAMP are proposed, including regulation of PDE4 isoforms by antidepressant treatment and development of PDE4 null mutant mice.